Resistance to Thyroid Hormone

Abstract

Resistance to thyroid hormone (RTH) is usually dominantly inherited and is characterized by elevated free thyroid hormones in the serum and failure to suppress pituitary thyroid stimulating hormone (TSH) secretion with variable refractoriness to hormone action in peripheral tissues. Two major forms of the disorder are recognized: asymptomatic individuals with generalized resistance (GRTH) and patients with thyrotoxic features, suggesting predominant pituitary resistance (PRTH). Molecular genetic analyses indicate that both GRTH and PRTH are associated with diverse mutations in the thyroid hormone receptor β gene, which localize to three regions in the hormone binding domain of the receptor. In addition to being functionally impaired, the mutant receptors are also able to inhibit their wild-type counterparts in a dominant negative manner. Recognized features of RTH include failure to thrive, growth retardation and attention-deficit hyperactivity disorder in childhood, and goitre and thyrotoxic cardiac symptoms in adults. The pathogenesis of variable tissue resistance is not fully understood but may be related to the differing tissue distributions of a and b thyroid hormone receptors and variable dominant negative activity of mutant receptors on different target genes.

Thyroid hormone receptors mutated in liver cancer function as distorted antimorphs

“…RTH-Syndrome TR mutants exhibit dominant-negative properties virtually identical to those described here for the HCC TR mutants, are expressed in a wide range of tissues, including hepatocytes, yet RTH Syndrome is not known to increase the incidence of HCC (Refetoff, 1993;DeGroot, 1996;Kopp et al, 1996;Chaterjee, 1997;. Notably, RTH-Syndrome mutations are characteristically single substitutions that map to the hormone-binding domain, whereas many of the HCC mutants have sustained multiple substitutions that encompass lesions in the DNA recognition domain of the receptor (Refetoff, 1993;DeGroot, 1996;Kopp et al, 1996;Chaterjee, 1997;Lin et al, 1999).…”

“…Inherited defects in TR function result in a human endocrine disorder, denoted Resistance to Thyroid Hormone (RTH) Syndrome (Refetoff, 1993;DeGroot, 1996;Kopp et al, 1996;Chaterjee, 1997;. RTH Syndrome is associated with mutations at the TRb locus that disrupt the triggering mechanism by which hormone binding induces corepressor release and coactivator acquisition (Yoh et al, 1997;Liu et al, 1998;Safer et al, 1998;Tagami and Jameson, 1998;Matsushita et al, 2000;Yoh and Privalsky, 2000).…”

Multiple mutations contribute to repression by the v-Erb A oncoprotein

“…Significantly, dominant-negative c-Erb A mutants do not appear to cause erythroleukemia in humans, but instead manifest as an endocrine disorder, RTH syndrome (Usala, 1991;Refetoff, 1993;DeGroot, 1996;Chaterjee, 1997). One notable distinction between the oncogenic v-Erb A and the non-leukemogenic RTH syndrome alleles is the multiplicity of the genetic lesions involved.…”

“…One notable distinction between the oncogenic v-Erb A and the non-leukemogenic RTH syndrome alleles is the multiplicity of the genetic lesions involved. In RTH syndrome, each mutant c-Erb A allele typically contains only single amino-acid difference from wild type (Usala, 1991;Refetoff, 1993;DeGroot, 1996;Chaterjee, 1997). The v-Erb A allele, in contrast, has sustained multiple genetic lesions relative to c-Erb A, including an Nterminal fusion of gag sequences, a C-terminal deletion, and 13 internal amino-acid substitutions (Sap et al, 1986).…”

“…As a consequence, v-Erb A can function as a dominant-negative inhibitor of c-Erb A function, and v-Erb A has been proposed to operate in the erythroleukemic cell by interfering with thyroid hormone signaling (Damm et al, 1989;Evans, 1989;Sap et al, 1989;Schroeder et al, 1992b;Samarut, 1996;Bauer et al, 1998;Stunnenberg et al, 1999;Thormeyer and Baniahmad, 1999;Urnov et al, 2000;Rietveld et al, 2001). However, simple dominant-negative mutants in human thyroid hormone receptors are associated with an endocrine disorder, resistance to thyroid hormone (RTH) syndrome, rather than neoplasia (Usala, 1991;Refetoff, 1993;DeGroot, 1996;Chaterjee, 1997). We therefore examined if the additional alterations sustained by v-Erb A relative to c-Erb A contribute to the oncogenic properties of the viral protein.…”